The U54 Cooperative Contraceptive Development Research Center Grant described for renewal in this application is comprised of five research and development projects. The goals are to identify and further develop new leads that look promising as safe and effective contraceptive methods for men and women: 1) A vaginal gel containing the microbicide Carraguard(TM) and the contraceptive steroid levonorgestrel (CARRA/LNG) will be further tested for dual protection against sexually transmitted infections and conception. One goal is to continue to test the product for use "on demand" before intercourse to delay or block ovulation in women having occasional sex. A low-dose formulation will target local effects of the progestin in thickening the cervical mucus, which inhibits sperm penetration, to be used by women having regular sex who need this progestin microbicide daily. 2) CDB-2914, a new progesterone receptor modulator with potent anti-ovulatory effects, will be further investigated in two projects;in one, new formulations of vaginal rings and intrauterine delivery systems (IUS) will be developed as "estrogen-free, bleed-free" contraceptives for women, and clinical studies will be pursued. The lowest effective dose to inhibit ovulation will be investigated in the ring studies. The IUS will target amenorrhea by direct action of a low dose of CDB- 2914 on the endometrium. The mechanisms of action of CDB-2914 to determine the underlying molecular pathways that are critically regulated by this PRM during ovulation will be examined. 3) In the other CDB- 2914 project, the safety and molecular mechanisms of CDB-2914 on human breast cells will be evaluated. The endometria of women exposed to the product in the clinical studies carried out in Project 2 will be evaluated for safety by means of pathological assessment and immunocytochemistry as well as flow cytometry and proteomics. 4) A tissue-specific androgen (MENT) with no effect on the prostate will be further evaluated for male contraception by means of a one-year implant used alone or in combination with a progestin. Mechanisms of the molecule on blood pressure, bone and fertility will be explored. 5) Finally, a new compound (Adjudin) has been identified that is able to induce reversible germ cell depletion from the rat testis. The overall goal is to explore the prospect of the Adjudin-FSH mutant conjugate's candidacy as a male contraceptive, by targeting germ cell adhesion. Alternative delivery routes will be studied.